Two male sibs with severe micrognathia and a missense variant in MED12

Trine E Prescott; Mari Ann Kulseth; Ketil R Heimdal; Barbro Stadheim; Einar Hopp; Tomasz Gambin; Zeynep H Coban Akdemir; Shalini N Jhangiani; Donna M Muzny; Richard A Gibbs; James R Lupski; Asbjørg Stray-Pedersen

doi:10.1016/j.ejmg.2016.06.001

Two male sibs with severe micrognathia and a missense variant in MED12

Eur J Med Genet. 2016 Aug;59(8):367-72. doi: 10.1016/j.ejmg.2016.06.001. Epub 2016 Jun 7.

Affiliations

¹ Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway. Electronic address: prescott@online.no.
² Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway.
³ Department of Radiology and Nuclear Medicine, Oslo University Hospital, 0424, Oslo, Norway.
⁴ Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA; Institute of Computer Science, Warsaw University of Technology, Warsaw, Poland.
⁵ Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.
⁶ Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA; Human Genome Sequencing Center (HGSC), Baylor College of Medicine, Houston, TX, 77030, USA.
⁷ Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA; Human Genome Sequencing Center (HGSC), Baylor College of Medicine, Houston, TX, 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, 77030, USA; Texas Children's Hospital, Houston, TX, 77030, USA.
⁸ Baylor-Hopkins Center for Mendelian Genomics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA; Norwegian National Unit for Newborn Screening, Oslo University Hospital, 0424, Oslo, Norway.

PMID: 27286923
DOI: 10.1016/j.ejmg.2016.06.001

Abstract

Missense variants in MED12 cause three partially overlapping dysmorphic X-linked intellectual disability (XLID) syndromes: Lujan-Fryns syndrome (also known as Lujan syndrome), FG syndrome (also known as Opitz-Kaveggia syndrome) and X-linked Ohdo syndrome. We report a family with two severely micrognathic male sibs, a 10½ year old boy and a fetus, in which hemizygosity for a previously unreported missense variant in exon 13 of MED12 (NM_005120.2), c.1862G > A, p.(Arg621Gln) was detected by whole exome sequencing. The affected sibs shared no other rare variant with relevance to the phenotype. X-chromosome inactivation in blood was completely skewed (100:0) in the unaffected heterozygous mother, most likely as a result of preferential inactivation of the X-chromosome harbouring the missense variant in MED12. Neither the unaffected brother nor the unaffected maternal grandfather carried the missense variant in MED12. In the 10½ year old boy, upper airway obstruction secondary to Pierre Robin sequence necessitated a tracheostomy for the first 10 months of life. He has mild to moderate intellectual disability and some dysmorphic features seen in MED12-related syndromes. In addition, he has a horizontal gaze paresis, anomalies of the inner ear, and a cervical block vertebra. This report contributes to the expanding phenotypic range associated with MED12-mutations.

Keywords: Intellectual disability; MED12; Mental retardation; Micrognathia; X-linked.

Publication types

Case Reports

MeSH terms

Exons
Genes, X-Linked
Genetic Association Studies
Genotype
Humans
Infant
Male
Mediator Complex / genetics*
Micrognathism / diagnosis*
Micrognathism / genetics*
Mutation, Missense*
Pedigree
Phenotype*
Polymorphism, Single Nucleotide
Severity of Illness Index
Siblings*
Tomography, X-Ray Computed
X Chromosome Inactivation

Substances

MED12 protein, human
Mediator Complex